Japnees Encephalitis & India

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Japanese encephalitis 505

J. Biosci.33(4), November 2008

1. Introduction

Japanese encephalitis is the most important form of epidemic

and sporadic encephalitis in the tropical regions of Asia

including Japan, China, Taiwan, Korea, Philippines, all of the

Southeast Asia and India; however related neurotropic viruses

are spread across the global (Solomon 1997). With the advent

of molecular virological techniques, it became clear that all the

flaviviruses share the common ancestry some 10- 20,000 years

ago and are emerging rapidly to fill the ecological niches (Gould

et al1997). Countries with the proven epidemics of Japanese

encephalitis (JE) are India, Pakistan, Nepal, Sri Lanka, Burma,Laos, Vietnam, Malaysia, Singapore, Philippines, Indonesia,

China, maritime Siberia, Korea, and Japan (Vaughn and Hoke

1992). In the past 50 years however; geographic area affected

by JE virus (JEV) has expanded. Epidemic activity in Northern

India, Central India and Nepal has increased since the early

1970s. Since 1990s the virus has continued to spread in

Pakistan (Igarashi et al1994), Nepal (Zimmerman et al1997),

and Australia (Hanna et al1996, 1999).

Two epidemiological patterns of JE are recognized. In

northern temperate regions of Asia, huge epidemics are

reported during summers while an endemic pattern of JE

is observed in southern tropical areas, where sporadic cases

occur throughout the year with the peak cases of encephalitisduring rainy season (Vaughn and Hoke 1992). Various

http://www.ias.ac.in/jbiosci J. Biosci.33(4), November 2008, 505514, Indian Academy of Sciences 505

Keywords. Japanese encephalitis virus; management; prevention; vaccine

Abbreviations used: CFR, case fatality rate; GM-CSF, granulocyte-macrophage colony-stimulating factor; JE, Japanese encephalitis; JEV,

JE virus; MHC, major histocompatibility complex; NS, non-structural; PHK, primary hamster kidney

Preventive strategies for frequent outbreaks of Japanese encephalitis in

Northern India

VANDANA SAXENA and TAPAN N DHOLE*

Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226 014, India

*Corresponding author (Fax, +91-0522-2668100; Email, [email protected])

Japanese encephalitis (JE) remains the most important cause of acute viral encephalitis and continues to spread

to hitherto unaffected regions like Indonesia, Pakistan and Australia. Approximately 60% of the world population

inhabits JE endemic areas. Despite its restricted range mostly in the developing countries, a high annual incidence of

50,000 cases and about 10,000 deaths has been reported. Disease can be fatal in 25% cases. Magnitude of the problem

is even more alarming since the survivors are left with serious long-term neuropsychiatric sequelae. Almost every two

years, epidemics of JE occur in Indian subcontinent with a high mortality. JE virus infection results in different diseasemanifestations in host from mild subclinical febrile illness to clinical infections leading to encephalitis. No antiviral

treatment is so far available for JE. The prevention of JE can be achieved by controlling the vector or by immunization

regime. The vector control in the rural areas, which are the worst affected ones, is practically almost impossible. Three

vaccines that have been implicated against JE include inactivated mouse brain derived, inactivated cell culture derived

and cell culture derived live attenuated JE vaccine. But each has its own limitation. Currently, attempts to synthesize

recombinant DNA vaccine are being made. New therapeutics are on the way of development like use of minocycline,

short interfering RNA, arctigenin, rosmarinic acid, DNAzymes etc. However, the immune mechanisms that lead to

JE are complex and need to be elucidated further for the development of therapeutics as well as safe and efficacious

JE vaccines.

[Saxena V and Dhole T N 2008 Preventive strategies for frequent outbreaks of Japanese encephalitis in Northern India;J. Biosci.33 505514]


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Vandana Saxena and Tapan N Dhole506


explanations have been offered to this incongruity. The most

likely reason is variation in the temperature pattern. In the

south, temperature remains high throughout the year with a

constant number of cases each month, however; a sharp rise

in temperature (above 200C) during summers in the north

corresponds to a sharp rise in the number of encephalitic

cases (Solomon et al2000).

2. Indian scenario

In India, JE is a major pediatric problem and epidemics

are reported from many parts. First clinical case of JE in

India was observed in 1955 at Vellore (former North Arcot

district, Tamil Nadu) (Namachivayam and Umayal 1982).

A total of about 65 cases were reported between 1955 and

1966 in South-India (Carey et al 1968). Since then many

major outbreaks have been reported from different parts,

predominantly in the rural areas. In 1973, the first major

outbreak occurred in Burdwan and Bankura, the twodistricts of West Bengal with about 700 cases and 300 deaths

(Chakravarty et al1975). Subsequently, another outbreak in

the same state occurred in 1976 with 307 cases and 126

deaths (Vaughn and Hoke 1992). Since then, virus is active

in almost all parts of India and outbreaks have been reported

from the states of Bihar, Uttar Pradesh, Assam, Manipur,

Andhra Pradesh, Karnataka, Madhya Pradesh, Maharashtra,

Tamil Nadu, Haryana, Kerala, West Bengal, Orissa and

union territories of Goa and Pondicherry (Kabilan et al

2004a). Presently, JE is not only endemic in many areas; it is

also spreading to nave non-endemic areas. JE has emerged

as a major public health problem in Kerala (Reuben and

Gajanana 1997). Epidemic of JE has occurred in AndhraPradesh during October-November, 1999 affecting 15 out of

23 districts with 873 cases and 178 deaths (Rao et al2000).

At the same time, 3 JE cases were reported for the first time

from two villages in Tamil Nadu (Victoret al2000). Later,

in July 2003 outbreak occurred in Warangal and Karim

Nagar districts of Andhra Pradesh (Das et al2004).

Outbreaks of JE has been reported from north-east regions

in Lakhimpur district of Assam between July-August, 1989.

It affected 90 villages of the district, covering a population of

approximately 36,000 and 50% case fatality rate (Vajpayee

et al1992). Later, several outbreaks are reported from Assam

in 3 consecutive years from August 2000-2002 (Phukan et

al2004). Diagnosis was confirmed in 53.7% patients with

ratios of 1.8:1 and 1.4:1 for male to female and pediatric to

adult patients respectively. Most of the cases were pediatrics

at the age of 7 to 12 years (34.2%).

In Northern states, the disease was reported to occur

between 1997 and 1981 (Vrati 2000). Gorakhpur region

(UP) experienced the most serious outbreak in 1988 with 875

cases (Rathi et al1993). An epidemic of viral encephalitis

was reported from July through November 2005 in

Gorakhpur. It was the longest and most severe epidemic in 3

decades; 5,737 persons were affected in 7 districts of eastern

Uttar Pradesh, and 1,344 persons died (Parida et al2006).A

total of 34 districts were involved (cases 5581, deaths 1593,

case fatality rate [CFR] 29). The affected districts decreased

to 22 districts in the year 2006 with lower CFR (cases 2075,

deaths 476, CFR 23) and in 2007, 24 districts were reportedwith 2675 cases, 577 deaths and CFR of 22. Gorakhpur,

Deoria, Kushinagar, Maharajganj, Basti, Sant Kabir

Nagar, Siddharth Nagar, Bahraich, Gonda, Saharanpur and

Muzaffar Nagar are the highly sensitive districts of JE.

Although JEV is RNA virus, neither any clinical pattern

has changed nor has any mutation in virus taken place. In

between we have noticed that the disease manifestations have

changed since 2005. The high incidence of encephalitis cases

is also attributable to non-JE cases as well with unidentified

etiologies and thus the cases can now be classified as JE/ non

JE. Among the non-JE cases, enterovirus 89 and 76 were

present in the CSF of encephalitis patients from Gorakhpur

in the year 2006.

3. Transmission

3.1 Mosquitoes

In a zoonotic cycle, JEV is transmitted by mosquito vectors

between wild and domestic birds and pigs. Mosquitoes

are vector as well as a crucial intermediate replicative

host for the normal enzootic cycle through birds and pigs.

Both pigs and birds like heron, ducks, chicks etc. support

high viremia and serve as the primary host for virus. Pigs

are amplifying hosts with no evident signs of infection.After acquiring the infection from viremic pigs and

completing the extrinsic cycle of 14 days, mosquito becomes

infectious. In these natural amplifying hosts, however; virus

does not produce encephalitis, although abortion occurs in

pregnant sows (Guerin and Pozzi 2005). Virus is transmitted

to humans by the bite of infected mosquito, which serves as

a dead end host due to its short duration and low viremia in

man (Schereret al1959). Humans are the incidental host and

not the natural host for JEV infections (Rosen 1986). The life

cycle of the virus is illustrated in figure 1.

Despite variation in geographic distribution of the virus,

mosquito vector species is relatively constant. Most important

mosquito vector in Asia is Culex tritaeniorhynchus whichbreeds in stagnant water like paddy fields or drainage ditches

(Innis 1995). Other species are Culex vishnui (India), C. gelidus,

C. fuscocephala (India, Malaysia, Thailand), C. pipiens.

3.2 Other routes

Besides mosquito, birds also serve to spread the virus to

new geographic areas. JEV is transmissible via semen in


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pigs which become asymptomatic with high level of viremia

(Guerin and Pozzi 2005). In both JE infected humans

(Chaturvedi et al 1980) and in experimentally infected

pregnant mice (Mathur et al 1981, 1982), transplacental

infection occurs and this mode of transmission results in

abortion of the embryos.

4. Seasonal pattern

Two epidemiological patterns of JE infection occur on the

basis of difference in the seasonal pattern. In the tropical

areas, endemic cases with sporadic cases throughout the

year while in temperate areas, seasonal incidence during

the monsoon/rainy season is marked from the month of July

to September. In India, Karnataka state experiences two

epidemics each year, a severe form from April to July and a

milder one from September to December along with the rest

of India (Vaughn and Hoke 1992).

Precipitation and temperature are two important

determinants of vector density that decide the disease

burden. At cooler temperatures, virus transmission rate

gets reduced. The reason being prolonged mosquito larvaedevelopment and longer extrinsic incubation duration at

lower temperatures.

5. High risk groups

Children and young adults are the mainly affected ones. Age

distribution of the disease varies with the region. Attack rates

in children (315 year age groups) are 510 times higher than

adults (


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behavioural disturbance and other such symptoms (Halstead

and Jacobson 2003).

There is an incubation period of 4-14 days in humans

during JEV infection and patients are presented with

few days of fever including coryza, diarrhea and rigors

(Solomon 1997). Headache, vomiting and reduced levels

of consciousness is followed by convulsions. A spontaneousrecovery is observed in a large proportion of patients, termed

as abortive encephalitis. In some patients, aseptic meningitis

with no encephalopathic features may appear (Solomon et

al2000). Convulsions occur more frequently in children in

upto 85% cases than in adult patients i.e. 10% (Kumaret al

1990). Other important features of JE patients are flat dull

mask like faces with wide unblinking eyes, tremors, and

cogwheel rigidity. Poliomyelitis like acute flaccid paralysis

(AFP) is also reported. About 30% of cases developed

encephalitis with reduced level of consciousness. Legs are

more affected than the arms (Solomon et al1998).

The clinical picture of this infection has four stages:

prodromal, acute, subacute and convalescent.

(i) Prodromal stage:

Lasts for 23 days.

Characterized by an abrupt onset of high fever

accompanied by headache, with non-specific

symptoms including malaise, anorexia, nausea

and vomiting.

(ii) Acute stage:

Lasts for 34 days.

Changes in the level of consciousness ranging

from mild clouding to stupors, semicoma or

coma.

Generalized or focal convulsions arecommon with neck stiffness and weakness of

extremities.

In this stage, fatal cases progresses rapidly and

die.

(iii) Subacute stage:

Lasts for 710 days.

Fever decreases with improved neurologic

sequelae in uncomplicated cases.

Secondary bacterial infections are common in

severe cases.

(iv) Convalescent stage:

Lasts for 47 weeks.

Complete recovery in mild cases. Severe cases improve but left with neurological

deficits.

7. Preventive measures

The prevention of JE can be achieved by controlling

the vector or by an immunization regime. To control the

vector population, spraying of an appropriate insecticide

should be carried out in the resting places of mosquitoes.

Thermal fogging with ultra low volume insecticides such

as pyrethrum or malathion has been recommended for

the prevention of local transmission during epidemics,

particularly in peri-urban areas with marshes. However;

the vastness of breeding places makes larvicidal measures

currently impracticable. Effective measures undertaken insome countries to prevent or inhibit larval development

include novel water management and irrigation practices

such as periodic lowering of the water level, intermittent

irrigation, and constant flow systems. Vector control alone

cannot be relied upon to prevent JE since it is practically

almost impossible to control mosquito density in the

rural areas which are the worst affected areas due to poor

socio-economic conditions (Tiroumourougane et al

2002). Therefore, the need is large scale immunization of

susceptible human population to prevent this deadly disease.

Mass scale vaccination can significantly reduce the disease

burden and incidence.

8. Current vaccines against JE

Three types of JE vaccine are currently in use: mouse-brain

derived inactivated, cell-culture derived inactivated and

cell-culture derived live attenuated JE vaccine. Formalin

inactivated vaccines are the safe and effective against JEV

for at least 30 years (Tsai 1999). Mouse-brain inactivated

vaccine is the most widely produced and internationally

distributed. The efficacy and the strain from which these are

produced are given in table 1.

8.1 Mouse-brain derived inactivated JE vaccine

Mouse-brain derived inactivated vaccine is the only

WHO approved vaccine against JE. It is produced from

Nakayama strain and Beijing-1 strain, the later strain is

in use of late due to its high cross-reactivity among the

JEV strain. Vaccine produced from the original Nakayama

strain, is manufactured in Japan and licensed in 1954.

It is available internationally under the Biken label

(Vaughn and Hoke 1992). This vaccine is also independently

produced in China, India, Thailand and Taiwan. Central

Research Institute, Kasauli is the manufacturer in India.



Table 1. Vaccines against Japanese encephalitis

Vaccine Strain Efficacy

Inactivated mouse brain Nakayama Beijing-1 91%

Inactivated primary hamster

kidney cells

P-3 85%

Live attenuated primary

hamster kidney cells

SA 14-14-2 >95%


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It is available in lyophilized form in which gelatin and

sodium glutamate is used as stabilizers and thimerosal as

preservative (Bharati and Vrati 2006). An efficacy of 91%

is reported in a study from Thailand with >65,000 children

(Hoke et al1988).

Although safe and effective, this vaccine has some

common side effects like erythema, swelling, tenderness,fever, headache, malaise and dizziness (Plesner 2003).

Further due to its high production cost, lack of long term

immunity and adverse allergic reactions, this vaccine is not

practical to administer in the poor rural areas, where the

vaccine is urgently needed. All these difficulties have led to

the development of improved vaccines.

8.2 Cell-culture derived inactivated JE vaccine

In China, an inactivated vaccine produced in primary

hamster kidney (PHK) cell culture was developed and

is in use since 1967. It is produced from the Beijing-P3strain. It has relatively less side effects and is easy to

manufacture. In an extensive randomized field trial in China,

its efficacy was found to range between 76-90% (Tsai et al

1999).

In the last decade, Vero cell-culture based inactivated

vaccine using various local JEV isolates has also been

developed and undergoing clinical trials. A vero-cell culture

derived formalin inactivated vaccine is being developed

using an attenuated SA14-14-2 strain and it induced high

titers neutralizing antibodies in mice after two injections

(Srivastava et al2001). Recently, vero cell-culture derived

formaldehyde inactivated JE vaccine using P 20778 (Indian

isolate) has been developed, which generated high titers ofanti-JEV antibodies in mice and sera from immunized mice

efficiently neutralized different JEV strains with different

efficacies (Appaiahgari and Vrati 2004).

8.3 Cell-culture derived live attenuated JE vaccine

Live attenuated vaccine appears to offer great prospects

for future vaccine development since less virus is needed

to mount a satisfactory immune response which makes the

vaccine cheaper and fewer doses are required which makes

it easy to administer (Solomon et al2000). In 1980s, China

developed a live attenuated vaccine named SA 14-14-2 by

passaging SA14 strain of JEV in PHK cells. Six amino acid

changes in E protein and three in NS genes were associated

with attenuation (Xin et al 1988; Ni et al 1994). In a

retrospective case control study, the vaccine efficacy was

reported 80% for a single dose and 98% with two doses

(Hennessy et al1996). Drawback of this vaccine is the PHK

substrate which is not approved by WHO for human vaccine

production.

9. Other JE vaccine under development

Several vaccine candidates are still in various stages of

development including recombinant protein based vaccines,

recombinant virus based/ chimeric vaccine and DNA

vaccines.

10. Recombinant protein based JE vaccines

E protein of JEV is important for various functions like

receptor binding and fusion and it is capable to induce

protective immunity. It is expressed in different expression

system in various forms. Its immunogenecity is then tested

in animal models, mice. Two expression vectors used for

this purpose are Escherichia coli (Seif et al 1995, 1996;

Saini and Vrati 2003; Rauthan et al2004) and baculovirus

expression systems (McCown et al1990; Yang et al2005).

11. Recombinant virus-based JE vaccine

Recombinant viruses are important in vaccine development.

A number recombinant viruses have been used, each have

their own unique feature. Induction of both humoral and

cell mediated immune response is the common factor in all

the recombinant/ chimeric vaccines. In this strategy, foreign

antigen is presented and processed by the host immune

system in the way similar to the natural infection. A number

of viruses have been used for the production of JE vaccines

including poxviruses (Konishi et al 1994; Kanesa-Thasan

et al2000), adenoviruses (Appaihagari et al2006), yellow

fever virus (Guirakhoo et al 1999; Monath et al 1999,2003).

12. DNA vaccines

In recent years, plasmid DNA vaccines gained much attention

due to their ability to generate a broad range of immune

responses, including antibodies induction, generation

of CD4 helper and CD8 cytotoxic lymphocytes and in

imparting protection against a range of viral infections (Kaur

et al2002). These vaccines are cost effective, safe and easy

to produce. These vaccines do not interfere with pre-existing

antibodies of other flaviviruses or vaccine vector. Here, the

DNA encoding a potent immunogen/ its part is placed undera bacterial plasmid under the control of a strong eukaryotic

promoter and then administered by different routes like

intramuscular or intradermal. There is plasmid endocytosis

followed by endogenous antigen production, which allows

its presentation by major histocompatibility complex (MHC)

class I and leads to production of CD8+ CTL response.

Also the uptake of soluble antigen by APC leads to

the generation of CD4+ Th response by MHC class II




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has also been tested and found to inhibit virus replication

in mouse brain (Appaiahgari and Vrati 2007). Recently,

therapeutic efficacy of a plant lignan, arctigenin is shown

both in vitro and in vivo. It has been reported that arctigenin

reduces the virus replication in brain along with reducing

neuronal death and secondary inflammation and oxidative

stress resulting from microglial activation (Swarup et al2008). However, the immune mechanisms that lead to JE are

complex and needs further elucidations for the development

of therapeutics as well as safe and efficacious vaccines.

14. Conclusion

There is no specific treatment for the disease, early

symptomatic management is important. Thus, what is needed

today is high vaccine coverage along with a strong and

active surveillance system. Though the ultimate objective

of surveillance is prevention of disease occurrence, the

immediate objective is detection of early warning signals

for any potential JE outbreak and initiate timely effective

control measures.

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